Dyspnea on exertion (DOE) and exercise intolerance are hallmark symptoms of heart failure with preserved ejection fraction (HFpEF). The mechanisms of these two symptoms are unknown. Potential mechanisms for DOE are numerous and multifactorial, including pulmonary limitations, exercise ventilatory limitations, central cardiovascular limitations, peripheral vascular/muscle limitations, autonomic control alterations, and lastly obesity. Obesity decreases lung volume subdivisions and exaggerates the age-related decline in maximal expiratory flow increasing the risk of expiratory flow limitation and dynamic hyperinflation during exercise, both responses associated with DOE. Obesity also increases the energy requirement of exercise, ventilatory demand, the work of breathing, and exercise intolerance; all these alterations can also influence DOE. Indeed, one third of obese adults experience DOE and many HFpEF patients are obese. DOE can be attenuated in adults by exercise training due to ?sensory adaptation. However, the effect of obesity in HFpEF patients is underappreciated, in contrast to conventional thinking, which assumes that increased pulmonary capillary wedge pressure (PCW) is responsible. The overall objective of Project 4 is to investigate the mechanisms of DOE and exercise intolerance in obese and nonobese HFpEF patients. Aim 1) We will examine the interaction of obesity (obesity-related alterations in pulmonary function & body composition including abdominal fat) and HFpEF (underlying changes in lung function) on ventilatory reserves at rest and during submaximal cycling exercise, and their associations (if any) with DOE and exercise intolerance in obese HFpEF patients as compared with nonobese HFpEF patients, and obese and nonobese patients without HFpEF. We hypothesize that breathing limitations due to obesity and HFpEF will combine to limit ventilatory reserves during exercise, which will provoke greater DOE and exercise intolerance in the obese HFpEF patients; Aim 2) We will investigate the effects of pulmonary vascular function (including the effects of decreased PCW via sublingual nitroglycerin, SL TNG, treatment,) on DOE and exercise tolerance during submaximal constant load cycling exercise (& during MR imaging for lung water content). We hypothesize that DOE may not be decreased as much by SL TNG treatment in obese HFpEF patients as in nonobese HFpEF patients since obesity-related respiratory limitations will not be altered by decreased PCW via SL TNG treatment; and Aim 3) We will examine the effects of central and peripheral exercise limitations via endurance exercise training coupled with SL TNG treatment (improved central cardiac function) and single leg kicking exercise training (improved peripheral muscle/vascular function) on DOE and exercise tolerance in HFpEF patients during constant load submaximal cycling exercise. We hypothesize that both central and peripheral exercise training will decrease DOE to a greater extent in obese HFpEF patients due to sensory adaptation (i.e., vs nonobese patients). Our long term goal is to understand the mechanisms of DOE and exercise intolerance in patients with HFpEF, and provide novel results that could alter conventional approaches for treating DOE in patients with HFpEF.